6-Hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride (arzoxifene hydrochloride) was first described generically in U.S. Pat. No. 5,510,357 ('357) and was specifically disclosed in U.S. Pat. No. 5,723,474 ('474). Both the '357 and '474 patents are incorporated herein by reference. Arzoxifene, whether in its free base or salt form, is a nonsteroidal mixed estrogen antagonist/agonist, useful for, inter alia, lowering serum cholesterol and for inhibiting hyperlipidemia, osteoporosis, estrogen dependent cancers including breast and uterine cancer, endometriosis, CNS disorders including Alzheimer's disease, aortal smooth muscle cell proliferation, and restenosis. The compound is currently undergoing clinical evaluation for the treatment and prevention of osteoporosis and the treatment of endometrial and breast cancer in women. Specifically, arzoxifene is useful for, and is being clinically evaluated for the treatment of receptor positive metastatic breast cancer; the adjuvant treatment of receptor positive patients following appropriate local or systemic therapy; the reduction of recurrence of invasive and noninvasive breast cancer; the reduction of the incidence of invasive breast cancer and ductal carcinoma in situ (“DCIS”). Arzoxifene is also useful in combination with radiotherapy; aromatase inhibitors, such as Aminoglutemide (CYTANDREN®), Anastrazole (ARIMIDEX®), Letrozole (FEMARA®), Formestane (LENATRON®), Exemestane (AROMASIN®), and the like; LHRH analogues, such as Goserlin (ZOLADEX®), Leuprolide (LUPRON®), and the like; and acetylcholinesterase inhibitors.
Arzoxifene is known to decompose over time as evidenced by the formation of degradation products, particularly an N-oxide degradation product and a cleavage degradation product. The formation of degradation products of an active pharmaceutical ingredient is typically undesirable. Such degradation products have the potential of untoward side effects and unnecessary exposure of the patients. The control of degradation products or impurities is regulated by International Conference on Harmonisation (ICH) guidelines as implemented by national regulatory authorities such as the United States Food and Drug Administration (FDA). The ICH guidelines delineate levels of such degradation products or impurities above which structural identification and qualification by appropriate toxicological or clinical studies must be performed.
Initial attempts at reducing the formation of degradation products of arzoxifene in a pharmaceutical composition were unsuccessful. The incorporation of the classical antioxidant molecule (ascorbic acid) actually augmented the formation of arzoxifene N-oxide degradation product, as well as the formation of other degradation products, with higher levels immediately after manufacture and a greater rate of increase during storage. As indicated in the pharmaceutical literature (see Akers M. J., Journal of Parenteral Science and Technology, 36(5):222–227 (1982)) there is no reliable method for predicting the effectiveness of antioxidant activity in pharmaceutical products.
We have now discovered that the addition of a stabilizing agent selected from methionine, acetylcysteine, cysteine or salts thereof as part of the pharmaceutical composition of arzoxifene tablets will greatly reduce the formation of degradation products during the manufacturing process and/or storage of the drug product.